Most anticancer agents clinically used at present have problems such as appearance of cancer cells with acquired resistance, i.e., anticancer agents that were effective formerly loose the effectiveness, and insufficient effectiveness against solid cancers. The tendency of the insufficient effectiveness of anticancer agents against solid cancers is considered to be caused by the activation or the like of transcription factors such as hypoxia inducible factor-1 (HIF-1) and nuclear factor κB (NF-κB) and resulting induction of excess expression of survival signals when a solid cancer grows larger than a certain size so as to cause internal hypoxic condition [Cancer, Res. 58, 1408 (1998)], and are activated to cause [Trends Mol. Med., 7, 345 (2001), Cell, 87, 13 (1996), Cell, 95, 729 (1998), Toxicology, 155, 27 (2000)]. However, details of the mechanism has not been clarified.
Under hypoxia (low oxygen pressure), a variety of genes, for example, erythropoietin which promotes generation of erythrocytes to increase oxygen supply to the whole body, VEGF and its receptor which stimulate angiogenesis to increase local oxygen supply, and genes of various enzymes in the glycolytic system which synthesize ATP in a condition without oxygen and provide resistance to cells, are activated to maintain homeostasis of oxygen. Hypoxia inducible factor-1 (HIF-1) is a chief transcription factor which performs transcription activation of these genes. Tumor tissues are in a low oxygen condition due to insufficient blood flow, and this low oxygen condition is known to accelerate angiogenesis. Accordingly, it is suggested that HIF-1 is deeply involved in angiogenesis.
Tumor necrosis factor α (TNF-α) is a major cytokine which exists in inflammatory sites and induces cell death through apoptosis. TNF-α stimulates generation of nuclear factor κB (NF-κB), and as a result, some types of cells have more potent resistance to the apoptosis signals. For example, in prostatic cancer and vesical cancer, cancer cells are hardly killed due to activation of NF-κB.
Therefore, if a substance is available that can inactivate HIF-1 or NF-κB which is excessively activated under a low oxygen condition or in an inflammatory site, the substance can be considered to be effective for preventive and/or therapeutic treatment of a solid cancer, chronic inflammation, and a variety of diseases caused by abnormal angiogenesis.